Despite decades of intensive study, the function of sleep is still not known. Similarly, our understanding of the molecules and mechanisms that govern sleep and wakefulness is incomplete. The recent identification of a sleep state in Drosophila melanogaster has opened up the possibility of using powerful forward genetic methods to dissect the function and regulation of sleep in a more accessible model organism. The specific aims of this proposal focus on two classes of mutants isolated in a forward genetic screen for Drosophila sleep mutants. One class of mutants exhibits a striking alteration of sleep phase and an increase in sleep duration. The second class exhibits reduced sleep. Genetic methods including crosses, meiotic mapping, and complementation testing will be employed to determine the properties of these mutants, including their mode of inheritance, chromosomal position, and relationship to already characterized genes that regulate sleep and the circadian clock. Additional behavioral and molecular characterization of these mutants will determine their arousal threshold, circadian period, and response to sleep deprivation. The final aim of this proposal is the molecular cloning of the affected genes underlying these sleep phenotypes, by means of deficiency noncomplementation, transgenic rescue, and gene sequencing. The molecular cloning of these genes will enable the structure, distribution, and activity of the encoded products to be studied and manipulated in future experiments. Ultimately, the broad objective of this research is to better understand the genes and mechanisms that underlie normal and dysfunctional sleep in humans. Public health relevance: The function of sleep is not known, and the mechanisms that control normal and dysfunctional sleep are not fully understood. The importance of understanding sleep is indicated by the cost of sleep related disorders, which is estimated at tens to hundreds of billions of dollars in the United States each year. This research will use a powerful genetic approach to broaden our understanding of genes that control sleep. [unreadable] [unreadable]